The present invention relates to intermediates for phosphonomethoxy nucleotide analogs, in particular intermediates suitable for use in the efficient oral delivery of such analogs.
Such analogs per se and various technologies for oral delivery of these and other therapeutic compounds are known. See WO 91/19721, WO 94/03467, WO 94/03466, WO 92/13869, U.S. Pat. Nos. 5,208,221, 5,124,051, DE 41 38 584 A1, WO 94/10539, WEJ7368583647920, WO 95 79/07919, WO 92/09611, WO 92/01698, WO 91/19721, WO 88/05438, EP 0 632 048, EP 0 481 214, EP 0 369 409, EP 0 269 947, U.S. Pat. Nos. 3,524,846 and 5,386,030, Engel, Chem. Rev. 77:349-367 1977, Farquhar et al., J. Pharm. Sci. 72:324-325 1983, Starrett et al., Antiviral Res. 19:267-273 1992, Safadi et al., Pharmaceutical Research 10(9):1350-1355 1993, Sakamoto et al., Chem. Pharm. Bull. 32(6):2241-2248 1984, and Davidsen et al., J. Med. Chem. 37(26):4423-4429 1994.
In accordance with this invention compounds are provided having formula (1a) ##STR1## wherein Z is independently --OC(R.sup.2).sub.2 OC(O)X(R).sub.a, and ester, an amidate or --H, but at least one Z is --OC(R.sup.2).sub.2 CO(O)X(R).sub.a ;
A is the residue of an antiviral phosphonomethoxy nucleotide analog;
X is N or O;
R.sup.2 independently is --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, axido, nitro or --OR.sup.3 in which R.sup.3 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl or C.sub.5 -C.sub.12 aryl;
R independently is --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkyenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, --N(R.sup.4).sub.2 or --OR.sup.3, where R.sup.4 independently is --H or C.sub.1 -C.sub.8 alkyl, provided that at least one R is not H; and
a is 1 when X is O, or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be --OR.sup.3 or (c) both N-linked R groups can be --H;
and the salts, hydrates, tautomers and solvates thereof.
Further embodiments of the compounds of this invention are compounds of formula (1) ##STR2## wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
R is independently --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR.sup.3 in which R.sup.3 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl or C.sub.5 -C.sub.12 aryl;
R.sup.1 is hydrogen, --CH.sub.3, --CH.sub.2 OH, --CH.sub.2 F, --CH.dbd.CH.sub.2, or --CH.sub.2 N.sub.3, or R.sup.1 and R.sup.8 are joined to form --CH.sub.2 --;
R.sup.2 independently is hydrogen or C.sub.1 -C.sub.6 alkyl; and
R.sup.8 is hydrogen or --CHR.sup.2 --O--C(O)--OR, or R.sup.8 is joined with R.sup.1 to form --CH.sub.2 --;
and the salts, hydrates, tautomers and solvates thereof.
Other embodiments comprise orally administering to a patient infected with virus or at risk for viral infection a therapeutically effective amount of a compound of formulas (1a) or (1).
Other embodiments of this invention include a method for preparing a compound of formula (1a) which comprises reacting the diacid of a phosphonomethoxy nucleotide analog with LC(R.sup.2).sub.2 OC(O)X(R).sub.a wherein L is a leaving group.
In particular embodiments of this invention, a method for preparing a compound of formula (1) is provided which comprises reacting a compound of formula (4) ##STR3## with LC(R.sup.2).sub.2 OC(O)X(R).sub.a.